16-halo steroids



United States Patent 0 3,027,383 16-HALO STEROIDS Donald E. Ayer,Kalamazoo, and William P. Schneider, Kalamazoo Township, KalamazooCounty, Mich. No Drawing. Filed Jan. 11, 1960, Ser. No. 1,419 20 Claims.(Cl. 260397.1)

This invention relates to certain novel 16-ha1o steroids and to aprocess for their production which can be represented by the followingstructural formulae:

(I) O O-lower-alkyl ICH ('10 O-lower-alkyl (IJH OH I Y=AcO--CH HO IwvIIIa (i7 0 0 -lower-a1ky1 CH IIIb (IJHB 0 H CH I HO F O i R E "ice (I30O-lower-alkyl via 16a-i0d0 compound O 0 O -lower-a1ky1 III 0 OO-lower-alkyl CH2 CH CH,OA FH2 311 0 0 I ----OH H0 F HO 1-1 /\CH3 A B Ol .nl H E.

VII VIII wherein Y is carbonyl, hydroxymethylene, orhydrocarbonacyloxymethylene, e.g., lower-"hydrocarbonacyloxymethylenecontaining from 1 to 12 carbon atoms, inelusive, in the acyl radical; Ris lower-alkylene, e.g., containing from 2 to 8 carbon atoms, inclusive,and containing from 2 to 3 carbon atoms in the oxygen to oxygen chain;Ac is the acyl radical of a hydrocarbon carboxylic acid, e.g.,containing from 1 to 12 carbon atoms, inclusive, and lower-alkyl meanscontaining from 1 to 8 carbon atoms, inclusive. The wavy line at the5-position is a generic expression which includes both the 5 8 (normal)and 5a (allo) isomers.

The compounds represented by Formulae I, II and III, wherein Y ishydroxymethylene or hydrocarbonacyloxymethylene, and Hit: ordinarilyhave a stereoconfiguration at the 5 position which is opposite that ofthe configuration of the 3-su'bstituent, e.g., 3,8-hydroxy-5u and3a-hydroxy-SB. The stereoconfigurtion of the side chain of CompoundsI-VII is preferably cis, although the corresponding trans isomers canalso be employed in the reactions described herein and are part of thisinvention. The trans isomers of the compounds represented by Formula Ican be prepared by refluxing the corresponding cis isomers in aloWer-alkanol containing an alkali-metal alkoxide, e.g., sodiummethoxide in methanol.

The compounds and process of this invention are useful in the productionof 21-ester-s of lfifl-fluorohydrocortisone, 16,8-fluoroprednisolone andcorresponding 90:,l6fi-difll10l'0 compounds. These compounds possessglucocorticoid, antiinflammatory and mineralocorticoid activity as wellas ACTH inhibiting, diuretic, CNS-regulating and progestationalactivity. They can be administered to the animal organism, e.g., man, aswell as birds and mammals, in the same fashion and in the samepharmaceutical forms as have been employed in the use of hydrocortisoneand hydrocortisone acetate, e.g., tablets, elixirs, solutions,suspensions, creams, and ointments.

The process of this invention comprises the step of reacting a l6a-bromocompound represented by Formula II, or the corresponding la-iodocompound, with a heavy metal fluoride, i.e., those metals havinginsoluble lbromides, e.g., copper, palladium, silver, platinum, gold,mercury, thallium and lead.

The 3-hydrocarbonacyloxymethylene-l6fl-fluoro compounds of thisinvention I (III, Y=Ae-0-(lJ H) can also be prepared from thecorresponding 3-hydroxy compounds (Illa) by esterification of the3-hydroxy group according to procedures well known in the art, e.g.,with the selected acid anhydride in pyridine. Similarly, the 3-hydroxycompounds (IIIa) can be prepared from the corresponding3-hydrocarbonacyloxy compound by an ester exchange reaction involvingthe latter compound, e.g., with boron trifluoride and methanol in themanner shown in Example 3. Oxidation of a 3-hydroxy compound (Illa)with, e.g., chromic acid or with a N-haloamide or N-haloimide inpyridine, is productive of the corresponding 3-keto compound (IIIb).

The novel 16a-bromo starting compounds for the proc ess of thisinvention (II) can be prepared by brominat ing, when Y is carbonyl orhydrocarbonacyloxymethylene, the corresponding 16-substituted compounds(I) with an N-bromoamide or N-bromoimide, e.g., N-brornoacetamide,N-bromosuccinimide, l,3-dibromo-5,5-dimethylhydantoin, desirably withconcommitant irradiation of the reaction mixture with actinic, e.g.,ultraviolet, light. Surprisingly, a good yield of the desired productcan be obtained when Y is carbonyl, although the 2 and/or 4 positionsare also susceptible to bromination.

The 16a-bromo starting compounds (II) wherein Y is hydroxymethylene canalso be prepared from the corresponding compounds wherein Y ishydrocarbonacyloxymethylene by removal of the ester group, e.g.,hydrolysis or preferably ester exchange reaction with methanol orethanol and boron trifluoride as the catalyst.

The loa-bromo starting compounds wherein Y is carbonyl can also beprepared by oxidation of the corresponding compound wherein Y ishydroxymethylene, e.g., with chromic acid or chromic oxide in sulfuricacid.

The compounds represented by Formula I are known in the art. See, forexample, US. Patent 2,752,366.

The l6 3-fluoro compounds of this invention are converted to115,17a,21-trihydroxy 16p fiuoro-4-pregnene 3,20 dione, 11/3,l7a,21trihydroxy l6fl-fluoro-lA- pregnadiene-3,20-dione and their 21-esters'bythe following reactions: a 3,1l-diketo-l613-fluoro-l7 (20)-pregnen-2loic acid lower-alkyl ester (IIIb) is ketalized with a loweralkyl 0'.- or{3- glycol under the usual reaction conditions, e.g., acid catalyst inrefluxing solvent with azeotropic removal of the water of reaction, toproduce the corresponding 3-cyclic ketal (IV). This ketal is thenreduced with a chemical reducing agent capable of reducing an estergroup to an alcohol, e.g., lithium aluminum hydride, lithium monomethoxy aluminum hydride, sodium aluminum hydride, to produce thecorresponding 3-ketal of 115,21 dihydroxy 16,8 fiuoro 17(20) pregnen 3-one (V). Hydrolysis of the 3-ketal group, e.g., with dilute aqueousmineral acid in a lower-alkanol followed by conventional Zl-acylation,produces the free 3-keto compound (VII). Oxidative hydroxylation of thiscompound with osmium tetroxide and another oxidizing agent whichcontributes an oxygen atom to the reaction, e.g., hydrogen peroxide, anamine oxide peroxide, an aryliodo oxide, alkyl peroxide or peracid,produces an l1B,l7a,2l-trihydroxy-l6,8-fluoropregnane-3,ZO-dione21-acylate (VIII). These compounds can be dehydrogenated chemically ormicrobiologically according to procedures known in the: art, e.g., withselenium dioxide, corynebacterium, Septomyxa atfinis, or mono ordihalogenated with bromine or an N-bromoamide or N-bromoimide andthendehydrdbrominated with base, e.g., pyridine, to produce thecorresponding A and A compounds, i.e., llB,17a,2l-trihydroxy 16hfiuoro-4-pregnene-3,ZO-dione 2l-acylate andllp,l7a,2l-trihydroxy-l6fi-fiuoro-l,4 pregnadiene 3,20.-

dione 21-acylate. Ester exchange reactions of these compounds withmethanol or ethanol in the presence of boron trifluoride as catalyst areproductive of the corresponding 2l-hydroxy compounds. Alternatively, a9u-fll10l'0 group can be introduced into these compounds by the usualsteps of dehydration of the llfi-hydroxy group, introduction of a 90cbromo llfl-hydroxy group with hypobromous acid, reaction with potassiumacetate to produce the 96,115-oxido group and then reaction withhydrogen fluoride to produce the 9a-fluor0-11fi-hydroxy compounds which,like the corresponding 9-hydrogen compounds, possess markedanti-inflammatory, glucocorticoid and mineralocorticoid activity.

PREPARATION 1 3a-Hydr0xy-11-Keto-5/8-Pregn-17 (20) [cis] -en-21- oicAcid Methyl Ester 3-A cetate 2.0 g. of3a-hydroxy-1l-keto-5/3-pregn-17(20)-[cis]-en- 21-oic acid methyl ester(US. Patent 2,752,366) was acetylated with 15 ml. of acetic anhydrideand 15 ml. of pyridine at room temperature overnight. The mixture waspoured into ice water and the precipitated steroid extracted withmethylene chloride. The extracts were washed with water, dilutehydrochloric acid, aqueous sodium bicarbonate, water and dried.Evaporation left a residue of 3/3-hydroxy-ll-keto-5B-pregn-17(20)-[cis]-en- 21-oic acid methyl ester 3-acetatewhich when, crystallized from hexanes, melted at 108-l11 C.

PREPARATION 2 3p-Hydr0xy-11-Ket0-5a-Pregn-17(20) -[cis] -en-21- oic AcidMethyl Ester Following the procedure of US. Patent 2,752,366, 3,8-hydroxy 5a pregnane-l1,20-dione [Cameron et al., J. Chem. Soc., 3864(1953)] was converted by the steps of glyoxalating with sodium methoxideand ethyl oxalate in tertiary butyl alcohol, diorominating with abouttwo molar equivalents of bromine in the presence of potassium acetate,and rearranging with sodium methoxide in methanol to 35-hydroxy11-ket0-5a-pregn'17(20)-[cis]-en-21- oic acid methyl ester which whencrystallized from ethyl acetate melts at 188190 C.

PREPARATION 3 3/3-Hydr0xy-11 -Keto-5a-Pregn-1 7 (20) [cis] -en-2l oicAcid Methyl Ester 3-A cetate Following the procedure of Preparation 1, 3B-hydroxy- 11-keto-5a-pregn-l7(20)-[cis]en-Zl-oic acid methyl ester wasacetylated to give 3B-hydroxy-ll-keto-h-pregn- 17(20)-[cis]-en-21-oicacid methyl ester S-acetate which, when crystallized from hexanes,melted at 143-145 C.

PREPARATION 4 3 ,1 1 -Diketo-5B-Pregn-1 7 (20 [cis] -en-21 -ic AcidMethyl Ester To a solution of 3.0 g. of 3u-hydroxy-ll-keto-Sfi-pregn-17(20)-[cis]-en-21-oic acid methyl ester in 400 ml. of acetone at 10 C.was added 2.4 ml. of 4 N chromic acid in aqueous sulfuric acid. Themixture was stirred for minutes and then poured into 2 l. of ice water.The precipitated 3,1l-diketo-5 8-pregn-l7(20)-[cis]-en-21-oic acidmethyl ester was collected and dried at reduced pressure to give 2.7 g.of crystals thereof melting at 213220 C. An analytical sample melting at213214 C. was obtained by crystallization from a mixture of acetone andhexanes.

Following the procedure of Preparation 4 exactly, but substituting 3fi-hydroxy-l 1-keto-5tr-pregn- 17 (20) [cis] -en- 21-oic acid methylester as the starting compound, there is thus produced3,11-diketo-5a-pregn-17(20)-[cis] en-2l- .oic acid methyl ester.

EXAMPLE 1 .ifi-Hydroxy-I 1 -Ket0-16a-Br0m0-5a-Pregn-l 7(20 [cis]en-Zl-oic Acid Methyl Ester 3-Acetate To a stirred solution of 2.8 g. of3/3-hydroxy-11-keto- 5a-pregn-l7(20)-[cis]-en-21-oic acid methyl ester3- acetate in ml. of boiling carbon tetrachloride in a glass flasktransparent to ultraviolet light Was added 1.31 g. ofN-bromosuccinimide. The mixture was irradiated with ultraviolet lightfor 10 minutes and then chilled to 10 C. The precipitated succinimidewas separated by filtration and the filtrate evaporated to dryness. Theresidual 3fi-hydroxy -11-'keto-16uromo-5a-pregn-17(20)- [cis]-en-Zl-oicacid methyl ester 3-acetate was crystallized from a mixture of acetoneand hexanes to give 2.75 g. of crystals melting at 195-197 C. Tworecrystallizations from a mixture of acetonitrile and water gave ananalytical sample melting at 197-200 C.

Following the procedure of Example 1, other loweralkyl ester 3-acylatesof 3p-hydroxy-11-keto-5 a-pregn- 17(20)-[cis]-en-21-oic acid, e.g.,methyl ester 3-propionate, methyl ester 3-octanoate, ethyl ester3-acetate, ethyl ester 3-propionate, ethyl ester 3-octanoate, arebrominated to produce the corresponding 16a-bromo compounds.

EXAMPLE 2 3 a-HydrOxy-I 1 -Ket0-1 6 oc-Br0m0-5 fi-Pregn-l 7 (2O [cis]-en-21-oic Acid Methyl Ester 3-A cetate Following the procedure ofExample 1, 1.4 g. of 3onhydroxy -11- keto 5B pregn -17(20) [cis] en 21oic acid methyl ester 3-acetate in 50 m. of carbon tetrachloride wasconverted with 0.66 g. of N-bromosuccinimide to 30 hydroxy 11 keto 16abromo 5,8 pregn-17(20)-[cis]-en-21-oic acid methyl ester S-acetate. Onecrystallization from hexanes gave 1.037 g. of crystals thereof meltingat 235-238 C. A second crystallization from a mixture of acetone andhexanes and two more from a mixture of acetonitrile and water droppedthe melting point of the analytically pure sample thus obtained to225-229" C., A max. 226 Ill t, E=8050, with a flex at 242 m E=7250.Infrared absorption bands (Nujol) were present at 1735, 1705, 1663, and870 cmr Following the procedure of Example 2, other loweralkyl ester3-acylates of 3u-hydroxy-1l-keto-Sfi-pregnl7(20)-[cis]-en-21-oic acid,e.g., methyl ester 3-propionate, methyl ester 3-octanoate, ethyl ester3-acetate, ethyl ester 3-propionate, ethyl ester 3-octanoate, arebrominated to produce the corresponding 16a-bromo compounds.

EXAMPLE 3 [cis] -en-21-0ic Acid Methyl Ester A solution of 0.4 g. of3u-hydroxy-11-keto-l6a-br om0- 5/3-pregn-17(20)-[cis]en-21-oic acidmethyl ester 3- acetate and 1 ml. of boron trifluoride etherate in 25ml. of methanol and 20 ml. of methylene chloride was maintained at roomtemperature for 18 hours. The solution was then concentrated at reducedpressure to 5 ml. and diluted with ml. of ice-water. The resultingprecipitate was collected and dried to give 0.313 g. of 3ahydroxy 11keto 16a bromo 55 pregn 17(20) [cis]-en-21oic acid methyl ester.

Following the procedure of Example 3, other loweralkyl ester 3-acylatesof 3a-hydroxy-11-keto-16ot-bromo- SB-pregn-l?(20)-[cis]-en-21-oic acidand the lower-alkyl ester 3-acylates ofSB-hydroxy-l1-keto-16a-bromo-5apregn-l7(20)-[cis]-en-21-oic acid, e.g.,methyl ester 3-propionate, methyl ester 3-octanoate, ethyl esterB-acetate, methyl ester 3-propionate, ethyl ester 3-octanoate, areconverted with boron trifiuoride in methanol to the correspondinglower-alkyl ester of3ot-hydroxy-11-keto-l6abromo-5B-pregn-17(20)-[cis]-en-2l-oic acid and3fl-hydroxy ll keto 16a bromo 5oz pr-egn 17(20) [cis] -en-21 acid,respectively.

EXAMPLE 4 3,11-Diket-16ot-Br0m0-5flPregn-1 7(20)-[cis1-en- 21-oic AcidMethyl Ester A solution of the 0.313 g. of3a-hydroxy-11-keto-16abromo-5B-pregn-17(20)-[ois]-en-21oic acid methylester, obtained in the manner described in Example 3, in 25 ml. ofacetone was cooled to C. and 0.2 ml. of a chromic acid and sulfuric acidsolution containing 1.1 mol. eq. of chromic acid, calculated on thesteroid, was added. After 10 minutes the reaction mixture was pouredinto 200 ml. of ice water. The precipitate was collected, washedthoroughly with water and dried to give 0.264 g. of white product which,when crystallized from a mixture of acetone and hexanes gave 0.22 g. of3,11-diketol6a-bromo-5 8-pregn-l7(20')-[cis]-en-21-oic acid methyl esterin two crops melting at 207-209 C.

Following the procedure of Example 4, other loweralkyl esters of3a-hydroxy-1l-keto-l6a-bromo-5B-pregnl7(20)-[cis]-en-21-oic acid and thelower-alkyl esters of 35 hydroxy llketo 16a bromo 5a pregn17(20)-[cis]-en-2l-oic acid, e.g., the ethyl, propyl, butyl, or octylester, are converted to the corresponding loweralkyl ester of3,1l-diketo-16a-bromo-5B-pregn-17(20)- [cis]-en-21-oic acid and of3,11-diketo-16a-bromo-5upregn-17( 20 [cis] -en2 l-oic, respectively.

EXAMPLE 5 3,11-Diket0-16a-Br0m0-5fi-Pregn-1 7(20) -[cis] -en- 21 -0icAcid Methyl Ester Following the procedure of Example 2 exactly, 1.4 g.of 3,11 diketo 5B pregn -17(20) [cis] en 21 oic acid methyl ester wasbrominated to give 3,11-diketo-16abromo-5B-preg'n-17(20)-[cis]-en-21-oic acid methyl ester. One crystallization from a mixture ofacetone and hexanes gave 0.856 g. of crystals thereof. Threecrystallizations from the same solvent pair gave an analytical samplemelting at 212214 C., A max. 227 mu, E=7900 with a flex at 244 m E=6800.The sample had infrared absorption bands (Nujol) at 1712, 1703, 1658 and870 cmr' Following the procedure of Example 5, other loweralkyl estersof 3,11-diketo-5B-pregn-17(20)-[cis]--en-21- oic acid and thelower-alkyl esters of 3,11-di-keto5upregn-17(20)-[cis]-en-21-oic acid,e.g., ethyl, propyl, butyl, octyl, etc., are brominated to produce thecorresponding lower-alkyl ester of 3,11-diketo-16a-bromo-5/3-pregn-17(20)-oic acid and of3,1l-dikelO-16a-bIOII10-5ocpregn-l7(20)-[cis]-en-21'oic acid,respectively.

EXAMPLE 6 3fl-Hydr0xy-1 I -Ket0-1 6p-Flu0r0-5a-Pregn-1 7 (20 [cis]-en-21-0ic Acid Methyl Ester S-Acetate A solution of 5.9 g. of3B-hydroxy-11-keto-16u-bromo- 5u-pregn-17(20)-[cis]-en-21-oic acidmethyl ester 3'-acetate in 275 ml. of acetonitrile containing 16 g. ofsilver bifluoride (prepared from anhydrous hydrogen fluoride and excesssilver oxide in acetonitrile) was heated under reflux for one hour. Themixture was cooled to room temperature, filtered and the filter cakewashed with methylene chloride. The filtrate Was evaporated at reducedpressure to a thick slurry which was partitioned between methylenechloride and water. The aqueous phase was separated and extracted withmethylene chloride. The combined methylene chloride phases were washedonce with water and dried. The solvent Was removed, leaving a 4.96 g.residue which was crystallized twice from a 50:50 mixture ofacetonitrile and water to give 3.49 g. of 3B hydroxy 11 keto 16,8 fluoro50c pregn 17(20)-[cis]-en-21-oic acid methyl ester 3-acetate melting at222228 C. An analytically pure sample, obtained upon furthercrystallizations, melted at 235235.5 C., had a x max. 214 mu, E=l4,400and infrared absorption (Nujol) bands at 1722, 1705, and 1665 cm'f 8EXAMPLE 7 3B-Hydroxy-11 -Ket0-16p-Fluoro-5u-Pregn-l 7 (20 [cis]-.en-21-0ic Acid Methyl Ester 3-Acetate (a) Following the procedure ofExample 6, 0.5 g. of 35 hydroxy 11 keto 16a brorno 5oz pregn17(20)-[cis]-en-21-oic acid methyl ester 3-acetate in 50 ml. ofacetonitrile was converted with 8 g. of a 50 percent aqueous silverfluoride solution during a two hour reflux period to3fl-hydroxy-1l-keto-l6p-fluoro-5u-pregnl7(20)-[cis]-en-2l-oic acidmethyl ester 3-acetate. One crystallization from a mixture ofacetonitrile and water gave 0.324 g. of crystals thereof melting at215-224 C.

(12) Similarly, 0.5 g. of the above-described starting material in 50ml. of acetonitrile was converted with 5 g. of solid silver fluoride tothe above-described reaction product. Work-up in the manner describedabove gave 0.278 g. of crystals thereof melting at 225-230 C.

(c) Similarly, a solution of 1.0 g. of the above-described startingmaterial in ml. of methylene chloride was refluxed for 19 hours in thepresence of mercuric fluoride to give the above-described reactionproduct. Work-up in the manner described above gave 0.51 g. of crystalsthereof melting at 228229 C.

Following the procedure of Examples 6 and 7, other lower-alkyl ester3-acylates of 3(3-hydroxy-1l-keto-16uhromo 5a pregn 17(20)[cis]-en-Zl-oic acid and the lower-alkyl ester 3-acylates of 3a-hydroxy11 ketol6a-bromo-5fi-pregn-17(20)-[cis]-en-2l-oic acid, e.g., the methylester 3-acetate, methyl ester 3-propionate, methyl ester 3-octanoate,ethyl ester 3-acetate, ethyl ester 3- propionate, ethyl ester3-octanoate, are converted to the corresponding lower-alkyl ester3-acylate of 3;.3-hydroxy- 1l-keto-l6B-fluoro-5a-pregn-l7(20)[cis]-en-Zl oic acid and 3a hydroxy 11 keto 16,8 fluoro 5a pregn-17(20) -[cis] -en-21oic acid, respectively.

EXAMPLE 8 3,11 -Diket0-16p-Flu0r0-5fi-Pregn-17(20) -[cis] -en-21-0icAcid Methyl Ester A solution of 1.78 g. of3,1l-diketo-lM-bromo-Sflpregn-17(20)-[cis]-en-21-oic acid methyl esterin ml. of acetonitrile containing 7.7 g. of silver bifluoride wasrefluxed for one hour and worked up in the manner described in Example 6to give 1.43 g. of 3,11-diketo-l6fifluoro-SB-pregn-ITQO)-[cis]-en-2l-oicacid methyl ester. This compound was converted to its 3-ethylene ketalin the manner described hereinafter. The purified ketal was hydrolyzedwith dilute sulfuric acid in acetone to give 3,11 diketo 16B fluoro 56pregn 17(20') [cis]-en- 21-oic acid methyl ester which, whencrystallized from a mixture of acetone and hexanes, melted at 158-159"C.

Following the procedure of Example 8, other loweralkyl esters of3,11-diketo-16a-bromo-5Bpregn-17(20)- [cis]-en-21-oic acid and thelower-alkyl esters of 3,11-diketo-l6a-bromo-5a-pregn47(20)-[cis]-en-2l-oic acid, e.g., the methyl,ethyl, propyl, butyl, octyl ester, are converted to the correspondingloWer-alkyl ester of 3,11- diketo-16l3-fluoro-5 ,8-pregn-17(20)-[cis]-en 21 oic acid and of 3,1l-diketo16fl-fluoro-5a-pregn-l7(20)-[cis1-en-21-oic acid, respectively.

EXAMPLE 9 3a-Hydr0xy-11-Ket0 16B Fluoro 56 Pregn 17(20)- [cis] 71-21-0ic Acid Methyl Ester .i-Acetate To 1.55 g. of3a-hydroxy-1l-keto-16a-bromo-5B-pregnl7(20)-[cis]-en-21-oic acid methylester 3-acetate in 50 ml. of boiling acetone was added 0.6 g. of sodiumiodide in 6 ml. of acetone. The mixture was refluxed for 30 minutes withstirring, cooled and diluted with 500 ml. of water. The mixture wasconcentrated at reduced pressure to remove the acetone and thenmaintained overnight at 5 C. The resulting yellow precipitate wascollected, washed with water and dried to give 1.66 g. of Sat-hydroxy-1l-keto-16a-i0do-5 fipregn-17(20) -[cis] -en 21 oic acid 9 methyl ester3-acetate. One crystallization from a 50:50 mixture of acetonitrile andwater gave 0.976 g. of crystals thereof melting at 195l98 C.

A mixture or" 1.366 g. of the thus-obtained crude iodo compound, 5 g. ofsilver bifluoride and 50 ml. of acetonitrile was refluxed for one hourand worked up in the manner described above. There was thus-obtained1.13 g. of 30c hydroxy -11 keto -16/3 fluoro 5e pregn -17(20)-[cis]-en-2l-oic acid methyl ester 3-acetate.

Following the procedure of Example 9, other loweralkyl esters of3,1l-diketo-l6a-bromo-5fl-pregn-l7(20)- [cis]-en-Zl-oic acid and thelower-alkyl esters of 3,11- diketo 16a bromo 5oz pregn 17(20) [cis] en-21-oic acid, e.g., the methyl, ethyl, propyl, butyl, octyl ester, areconverted via the corresponding 16-iodo compound to the correspondinglower-alkyl ester of 3,11- diketo 16,8 fluoro 5B pregn 17(20) [cis] en-2l-oic acid and of 3,1l-diketo-l6fi-fluoro-5a-pregn-17- (20)-[cis]-en-21-oic acid, respectively. Similarly, the compounds of Examples l3are concerted to the corresponding l6,8fluoro compounds by reaction withsodium iodide in acetone followed by reaction of the thus-produced16ot-iodo compounds with silver bifluoride in .acetonitrile.

EXAMPLE 10 3a-Hydr0xy-1 1-Ket0]6fl-Flu0r0-5B-Pregn-1 7 20 [cis] err-21-oic Acid Methyl Ester A solution of 1.08 g. of the3a-hydroxy-ll-keto-16B- fluoro-Sfi-pregn-17(20)-[cis]-en-21-oic acidmethyl ester 3-acetate, obtained according to the procedure of Example9, in 50 ml. of methanol and 1 ml. of boron trifluoride etherate wasrefluxed for one hour. The solution was cooled to room temperature,evaporated to 5 ml. at reduced pressure and then diluted to 100 ml. withice and water. After two hours at 5 C. the precipitate was collected,washed well with water and dried at reduced pressure to give 0.917 g. of3m-hydroxy-11-keto-16fi-fluoro-5B- pregn-17 (20)-[cis]en-21-oic acidmethyl ester.

Following the procedure of Example 10, other loweralkyl ester 3-acylatesof 3a-hydroxy-1l-keto-16-fiuoro- 5,8pregn17(20)-[cis]-en-21-oic acid,e.g., methyl ester 3- propionate, methyl ester S-octanoate, ethyl ester3-acetate, ethyl ester 3-propionate, ethyl ester 3-octanoate, areconverted to the corresponding lower-alkyl ester of 3ahydroxy-l l-keto-1 6,8-fiuoro-5fi-pregn-l7 20) [cis] -en-21 oic acid.

EXAMPLE l1 3,11-Diket-1 6fl-Fluor0-5fl-Pregn-1 7(20) [cis] -en-21-0icAcid M efhyl Ester A solution of 0.917 g. of3cx-hydroxy-11-keto-16fl-fluoro- B-pregn-17(20)-[cis]-en-2l-oic acidmethyl ester, obtained according to the procedure of Example 10, in 12ml. of acetone was cooled to C. and 0.65 ml. of 4 N chromium trioxide insulfuric acid and Water was added. After 15 minutes the mixture wasdiluted with 100 ml. of ice water and then maintained overnight at 5 C.The resulting precipitate was collected, washed with water and dried togive 0.836 g. of 3,1ldiketo-l6fi-fiuoro-5,8-pregn-17(20)-[cis]-en-21-oic acid methyl ester. This compound wasconverted to its 3-ethylene ketal in the manner described hereinafterand then hydrolyzed with dilute sulfuric acid in acetone to the free3-ketone to give 0.486 g. of crystals thereof melting at 157-159 C.

Following the procedure of Example 11, other loweralkyl esters of3a-hydroxy-11-l eto-16[i-fluoro-5/i-pregn- 17(20)-[cis]-en-2loic acid,e.g., ethyl, propyl, butyl, octyl ester, are oxidized to thecorresponding loWer-alkyl ester of3,1l-diketo-16/3-fiuoro-5fi-pregn-l7(20)-[cis]-en- 21-oic acid.

EXAMPLE 12 3B-Hydr0xy-11 -Ket0-16/3-Fluor0-5u-Pregn-17 [cis]-en-ZI-oicAcid Methyl Ester To a solution of 3.46 g. of 3B-hydroxy-11-keto-16fl-10 fiuoro-5a-pregn-17(20)-[cisJ-en-21-oic acid methyl ester 3-acetate in70 ml. of methylene chloride and 200 ml. of methanol was added 7.0 ml.of boron trifluoride etherate. The mixture was maintained at roomtemperature for 22 hours and then diluted with 900 ml. of ice Water. Theresulting precipitate was collected and dried to give 3.04 g. of 35hydroxy 1l-keto-l6 8-fluoro-5a-pregn-17 (20)-[cis]en-21-oic acid methylester.

Following the procedure of Example 12, other loweralkyl ester 3-acylatesof 3fl-hydroxy-ll-keto-l65-fluoro- 5a-pregn-17(20)-[cis]-en-2l-oic acid,e.g., methyl ester 3-propionate, methyl ester 3-octanoate, ethyl ester3-acetate, ethyl ester 3-propionate, ethyl ester 3-octanoate, areconverted to the corresponding lower-alkyl ester of 3;?- hydroxy 11 keto16fi-fluoro-5a-pregn-17(20)-[cis1-en- 21-oic acid.

EXAMPLE 13 3,1 1 -Diket0-16,8-Flu0r0-5a-Pregn-1 7(20 [cis] -en- 21-0icAcid Methyl Ester The 3 B hydroxy 1l-keto-l6fi-fluoro-5a-pregn-17(20)-[cis]-en-Zl-oic acid methyl ester obtained according to the procedure ofExample 12 was dissolved in 150 ml. of acetone and cooled to 10 C., 2.3ml. (1.1 mol. eq.) of a solution prepared from 26.7 g. of chromic oxideand 26 ml. of sulfuric acid diluted to ml. with Water was added and themixture was stirred for 15 minutes with cooling. The reaction mixturewas poured into 1,800 ml. of ice water which was then maintained at 5 C.for 24 hours. The resulting precipitate was collected, washed thoroughlywith water and dried to give 2.75 g. of 3,11- diketo 16Bfiuoro-5a-pregn-17(20)-[cis]-en-21-oic acid methyl ester.Crysatllizations from mixtures of acetone and hexanes and fromacetonitrile and water gave 2.5 g. of crystals thereof melting at209-213 C. An analytical sample thereof, obtained by a furthercrystallization from a mixture of acetonitrile and water, melted at213-214 C., 7\ max. 214 m E=14,400, and had infrared absorption spectrumbands (Nujol) at 1705 and 1660 cm.*.

Following the procedure of Example 13, other loweralkyl esters of3B-hydroxy-1l-keto-l6B-fluoro-5a-pregn- 17(20)-[cis]-en-2l-oic acid,e.g., ethyl, propyl, butyl, octyl ester, are oxidized to thecorresponding lower-alkyl ester of 3,l1-diketo-16fl-fluoro-5a-pregn-17(20)[cis]-en 21-oic acid.

EXAMPLE 14 3,11-Diketo-16p-Flu0r0-5a-Pregn-17(20) -[cis]-en- 21-0ic AcidMethyl Ester 3-Ethylerze Ketal A solution of 1.42 g. of3,11-diketo-16/8-fluoro-5oc1 pregn-17(20)-[cis]-en-21-oic acid methylester, 2 ml. of ethylene glycol and 50 mg. of p-toluenesulfonic acid in200 ml. of benzene was refluxed with azeotropic removal of Water for 3hours. The solution was then cooled to 40 C. and 0.2 ml. of pyridine wasadded. The cooled solution was Washed With water, dried and the solventremoved at reduced pressure. There was obtained, after onecrystallization from a mixture of benzene and hexanes, 1.32 g. of3,1l-diketo-l6fi-fluoro-5u-pregn-l7(20)- [cis]-en-21-oic acid methylester 3-ethylene ketal melting at 255260 C.

Following the procedure of Example 14, other loweralkyl esters of3,11-diketo-l6fl-fluoro-5a-pregn-17(20)- [cis]-en-Zl-oic acid, e.g.,ethyl, propyl, butyl, octyl ester, are converted to the corresponding3-ethylene ketal thereof.

Substituting another lower-alkylene ocor B-glycol for the ethyleneglycol in the reaction, e.g., propylene glycol, trimethylene glycol,butylene-2,3-glycol, produces the corresponding 3-lower-alkylene glycolof 3,11-diketo-16/3- fluoro-5u-pregn-17(20)-[cis]-en-2l-oic acid methylester. Other lower-alkyl esters are similarly converted to their3-lower-alkylene ketals.

1 1 EXAMPLE 15 3 ,1 1 -Diket-1ofi-Fluorodfl-Pregn-l 7 (20) -[cis] -en-21 -oic Acid Methyl Ester 3-Eethylene Kezal A solution of 1.43 g. of3,11-diketo-16B-fluoro-5B- pregn-17(20)-[cis]-en-21-oic acid methylester, 3 ml. of ethylene glycol and 70 mg. of p-toluenesulfonic acid in60 ml. of benzene was refluxed for /2 hours with azeotropic removal ofwater. The product was worked up in the manner described in Example 14to give, after crystallization from a mixture of acetone and hexanes,1.11 g. of 3,11 diketo 1613-fluoro-5/3-pregn-l7(20)-[cis]-en-2l oic acidmethyl ester 3-ethylene ketal melting at 222- 223 C. Furthercrystallization from the same solvent mixture gave an analytical samplemelting at 223-225 C.

Following the procedure of Example 15, other loweralkyl esters of3,11-diketo-16fi-fluoro-5[3-pregn-17(20)- [cis]-en-21oic acid, e.g.,ethyl propyl, butyl, octyl ester, are converted to the corresponding3-ethylene ketal thereof.

Substituting another lower-alkylene 06- or fl-glycol for the ethyleneglycol in the reaction, e.g., propylene glycol, trimethylene glycol,butylene-2,3-glycol, produces the corresponding lower-alkylene glycol.Other lower-alkyl esters are similarly converted to their3-lower-alkylene ketals.

EXAMPLE 16 1 15,21 -Dihydr0xy-1 6 ,B-F lu0r0-5 fiPregn-I 7 (20 [en]3-0ne and 3-Etlzylene Ketal and 21 -A aerate Thereof A solution of 0.908g. of 3,11-diketo-l6fl-fiuoro-55- pregn-l7(20)[cis]-en-21-oic acidmethyl ester S-ethylene ketal in 50 ml. of tetrahydrofuran was addedover a minute period at 10 C. to 0.122 equivalents of monomethoxyllthiumaluminum hydride in 85 ml. of tetrahydrofuran. The mixture was stirredfor 2 hours at 0 C. and then ethyl acetate followed by water werecautiously added. The solids were filtered and washed thoroughly withhot ethyl acetate. The filtrate was evaporated, leaving a residue of1113,2l-dihydroxy-lfl-fluoro- SB-pregn-l7(20)-[en]-3-one S-ethyleneketal.

The thus-produced 3-ethylene ketal was dissolved in 50 m1. of acetone, 5ml. of 5% sulfuric acid was added and the solution was maintained for 18hours at room temperature and then diluted with water. The mixture wasadjusted to ph 6 and then concentrated at reduced pressure. Theconcentrate was extracted with methylene chloride which was then driedand evaporated to give a 0.62 g. residue of115,21-dihydroxy-l6fi3-fluoro-5fi-p1egn- 17(20)-[cis]-en-3-one.

The thus-produced compound was acetylated at room temperature for 18hours with 4 ml. of acetic anhydride and 2 ml. of pyridine. The mixturewas then flooded with ice water and the precipitated steroid separated,washed with water, dilute hydrochloric acid, aqueous sodium bicarbonate,water and dried to give 0.618 g. of l13,2l-dihydroxy-16B-fiuoro-5f3-pregn-l7(20)- [cis]-en-3- one 21-acetatewhich was chromatographed on 25 g. of magnesium silicate. The column wasdeveloped with SO-ml. portions of hexanes containing 10% acetone.Fractions 3-8 contained 543 mg. of the desired product having infraredabsorption bands at 3620, 3520, 1740, 1728, 1712 and 1240 cmf Followingthe procedure of Example 16, other loweralkyl esters of3,1l-diketo-l6B-fiuoro-5fi-pregnd7(20)- [cis]-en-2l-oic acid 3-ethy1eneketal, e.g., the ethyl, propyl, butyl, or octyl ester, are alsoconverted to the 3- ethylene ketal of11,8,2l-dihydroxy-l6[3fiuoro-5{3-pregnl7(20)-[cis]-en-3-one.

Substituting another 3-lower-alkylene ketal of loweralkyl esters of3,1l-diketo-l6,6-fluoro-55-pregn-17(20)- [cis]-en-21-oic acid, e.g.,ethylene ketal ethyl ester, ethylene laetal octyl ester, trimethyleneketal methyl ester, trimethylene ketal ethyl ester, propylene ketalmethyl ester, propylene ketal ethyl ester, for the 3-ethyleue ketal 12methyl ester of 3,1l-diketo-l6fl-fluoro-5B-pregn-17(20)- [cis]-en-21-oicacid, there is produced the corresponding lower-alkylene ketal of115,2l-dihydroxy-16,8-fluoro-518- pregn-17(20)-[cis]-en-3-one. Each ofthe above loweralkylene ketals are hydrolyzed in the same manner as theB-ethylene ketal to produce 115,2l-dihydroxy-lop-fiuoro-J'fl-pregn-17(20)-[cis]-en-3-one.

Similarly, 11,8,21-dihydroxy-16fl fluoro 55 pregn- 17{20)-[cis]-en-3-oneis converted to other 21-acylates thereof by esterification of the21-hydroxy groups, e.g., by reaction with the appropriate acidanhydride, acid chloride or bromide, ester by ester exchange, acid inthe presence of an esterification catalyst, etc. Examples of the21-acylates thus prepared include those wherein the acyl group is theacyl radical of, for example, a loweraliphatic acid, e.g., formic,propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic,Z-methylbutyric, 3- ethylbutyric, hexanoic, diethylacetic,triethylacetic, heptanoic, octanoic, or-ethyl-isovaleric, a cyclic acid,e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g.,cyclopentylforrnic, cyclopentylacetic, B-cyclopentylpropionic,cyclohexylformic, cyclohexylacetic, li-cyclohexylpropionic, an aryl oralkaryl acid, e.g., benzoic, 2, 3, or 4- methylbenzoic, 2,3-, 2,4-,2,5-, 2,6-, 3,4- and 3,5-dirnethylbenzoic, ethylbenzoic,2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic, a-naphthoic,3-methyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic,phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (whichcan be converted to water soluble, e.g., sodium, salts), e.g., succinic,giutaric, ct-methylglutaric, fi-methylglutaric, [3,,B-dimethylglutaric,adipic, pimelic and suberic acid.

EXAMPLE 17 116,21-1) ihydroxy-l 6fi-Flu0r0-5ot-Pregn-1 7 (20 -[cis] -en-3-0ne and 3-Ethylene Ketal and S-Acetate Thereof A solution of 2.56 g.of 3,1l-diketo-lGB-fluoro-hpregu17(20)-[cis]-en-21-oic acid methyl ester3-ethylene ketal in ml. of tetrahydrofuran was added over a 10-minuteperiod to a stirred suspension of 2.7 g. of lithium aluminum hydride in400 ml. of tetrahydrofuran at 0 C. Stirring was continued at ice-bathtemperature and the mixture was decomposed by the cautious addition of 7ml. of water. The mixture was filtered and the filter cake was washedthoroughly with hot ethyl acetate. The filtrate was evaporated to give2.07 g. of 115,21-dihydroxy 16B fiuoro-5a-pregn-17(20) -[cis]-en3-0ne 3-ethylene ketal melting at 160-173 C.

The thus-obtained ketal was dissolved in ml. of acetone and 15 ml. of 3%sulfuric acid was added. The solution was maintained overnight at roomtemperature and then neutralized with aqueous sodium bicarbonate. Theacetone was evaporated at reduced pressure and the product extractedwith methylene chloride which was then washed with water and dried. Thesolvent was removed at reduced pressure to give a residue of1l[:,2ldihydroxy-l65-iluoro-5wpregn-17(20)-[cis]-en-3-one.

This product was maintained in a mixture of 5 ml. of acetic anhydrideand 7 ml. of pyridine at room temperature for 20 hours. The mixture wasthen poured into 500 ml. of ice water and the resulting precipitate wascollected, dissolved in methylene chloride, washed with water, dilutehydrochloric acid, aqueous sodium bicarbonate, water and then dried togive 2.02 g. of 11,8,21-dihydroxy-lofl-fluoro5a-pregn-17(20)-[cis]-en-3-one 21- acetate. An analytical sample thereofmelting at 137- 139" C. was obtained by crystallization from a mixtureof acetone and hexanes.

Following the procedure of Example 17, other lowerall iyl esters of3,1l-diketo-16,8-fluoro-5a-pregd-17(20)- [cisJ-eu-Zl-oic acid 3-ethyleneketal, e.g., the ethyl, propyl, butyl, or octyl ester, are alsoconverted to the ethylene ketal of11(3,2l-dihydroxy-l6,3-fluoro-5a-pregn- 17(20)-[cis]-en-3-one.

Substituting other 3-lower-alkylene ketals of loweralkyl esters of3,1l-diketo-l6/3-1luoro-5a-pregn-17(20)- [cis]-en-21-oic acid, e.g.,ethylene ketal ethyl ester, ethylene ketal octyl ester, trimethyleneketal methyl ester, trimethylene ketal ethyl ester, propylene ketalmethyl ester, propylene ketal ethyl ester, for the 3-ethylene ketalmethyl ester of 3,1l-diketo-l6,3-fluoro-5a-pregn-17(20)- [cis]-en-21-oicacid, there is produced the corresponding lower-alkylene ketal of115,21-dihydroxy-16;8-fluoro-5apregn-l7(20)-[cis]-en-3-one. Each of theabove loweralkylene ketals are hydrolyzed in the same manner as theethylene ketal to produce 115,21-dihydroxy-16fl-fluoro-5u-pregn-l7(20)-[cis] -3-one.

Similarly, 1113,21 dihydroxy 16,8 fluoro 5oz pregn- 17(20)-[cis]-en-3-one is converted to other 21-acylates thereof byesterification of the 21-hydroxy group with the appropriate acidanhydride, acid chloride or bromide, ester by ester exchange, acid inthe presence of an esterifioation catalyst, etc. to produce 21-acylateswherein the acyl radical is, for example, that of an acid named in theparagraph following Example 16.

EXAMPLE 18 1 16,1 7 06,2 1 -Trihydrxy-1 6,8-Flu0r0-5a-Pregn an e-3,20-Dione ZLAcetate To a solution of 0.474 g. of crude 115,21-dihydroxy- 16pfiuoro-apregn-17(20 )-[cis]-en-3-one ZI-acetate in 25 ml. of tertiarybutyl alcohol was added 0.3 ml. of pyridine, 5.2 molar equivalents ofN-methylmorpholine oxide peroxide and 13 mg. of osmium tetroxide in 6ml. of tertiary butyl alcohol. After 20 hours at room temperature, 30ml. of 0.5 percent aqueous sodium hydrosulfite was added and the mixturewas stirred for 30 minutes. The solution was concentrated at reducedpressure and extracted with methylene chloride. The extracts were washedwith a brine solution and dried. The solvent was evaporated and theresidue redissolved in 10 ml. of methylene chloride which was pouredover a magnesium silicate (Florisil) chromatographic column. The columnwas developed with 50-ml. portions of hexanes containing increasingportions of acetone, viz. 10 with 5% acetone, 20 with 10% acetone and 20with acetone. The last 10 50-ml. eluate portions with 10% acetone andthe first three with 15% acetone eluted l1,8,170:,21-(1ihYdI'0XY-L6flfluoro 5a pregnane 3,20- dione 21-acetate which, when crystallized froma mixture of acetone and water, melted at l84-186 C. An analyticalsample obtained by recrystallization from a mixture of acetone andhexanes melted at 190-193 C.

Similarly, other 21-acylates of 11,3,21-dihydroxy-16B-fluOro-Su-pregn-17(20)-[cis]-en-3-one, e.g., wherein the acyl radicalthereof is that of an acid named in the paragraph following Example 16,are converted to the corresponding 21 acylate of 11,8,17a,21 trihydroxy16B- fluoro-5a-pregnane-3,20 dione.

EXAMPLE 19 1 15,1 7a,21 -Trihydroxy-l 6B-Flu0ro-5p-Pregnane-3,20- Dione21 Acetate To a solution of 0.543 g. of 115,2.1-dihydroxy-16B-fiuoro-5B-pregn-17(20)-[cis]-en 3 one 21-acetate in 36 ml. of tertiarybutyl alcohol was added 0.8 ml. of pyridine, 3.0 mol. eq. ofN-methylmorpholine oxide peroxide and 4.7 mg. of osmium tetroxide in 1.5ml. of tertiary butyl alcohol. The stirred mixture was maintained atroom temperature for 19 hours and to it was then added 50 ml. of 0.5percent aqueous sodium hydrosulfite. The mixture was then concentratedat reduced pressure to 15 ml. and extracted with methylene chloride. Theextracts were washed with a brine solution, dried and evaporated todryness. The residue was redissolved in 15 ml. of methylene chloride andchromatographed on a 25 g. column of magnesium silicate. The column wasdeveloped with 50-ml. portions of hexanes containing 10% acetone.Fractions 8-23 were freed of solvent to give 14l15,17a,21-trihydroxy-16,B fluoro 5B pregnane 3,20- dione ZI-acetate.

Similarly, other 2l-acylates of11,3,21-dihydroxy-16fiiluoro-5fi-pregn-17(20)-[cis]-en-3-one, e.g.,wherein the acyl radical is that of an acid named in the paragraphfollowing Example 16, are converted to the corresponding 21-acylate of11/3,17a,21-trihydroxy-16fi fluoro 55- pregnane-3,20-dione.

1 1,8,1 7a,21-Trihydroxy-165-Flu0r0-4-Pregncue-3,20- D tone 2] -Acetate0.02 ml. of bromine was added over a 30 second period to a solution of0.145 g. of 11/3,17ot,2l-trihydroxy-16fifluoro-Sfl-pregnane-B,20-dione21-acetate in 6 ml. of purified dioxane containing 5 mg. ofp-toluenesulfonic acid monohydrate. After 3 minutes the solution wasdiluted with aqueous sodium bicarbonate to 125 m1. and cooled for 1 hourat 5 C. The mg. of precipitated 4-bromo- 11,3,17,21-trihydroxy-L6pfluoro 5,3 pregnane 3,20- dione 21-acetate was separated and dried.Extraction of the mother liquors gave an additional mg. of the sameproduct.

A mixture of the 170 mg. of the thus-obtained 4-bromo compound, mg. ofsemicarbazide hydrochloride, 120 mg. of sodium acetate and 31 ml. of 98%acetic acid was heated at 40-90 C. under nitrogen for 2 hours. Thethus-obtained solution of 3-sernicarbazide of 11,8,l7a,21-trihydroxy-l6fi-fiuoro-4-pregnene 3,20-dione 21-acetate Was decomposedby adding 1.75 ml. of pyruvic acid in 3.5 ml. of water thereto andcontinuing the heating for 1.5 hours at 60-90 C. The solution Was thencooled, diluted with 200 ml. of ethyl acetate and extracted with icecold 1 N aqueous sodium hydroxide. The ethyl acetate layer was dried andthen evaporated to give a residue of 11B,l7a,21-trihydroxy-16p-fluoro 4pregnene 3,20- dione ZI-acetate which, when purified by chromatographyon magnesium silicate in the manner described hereinbefore and thencrystallized from a mixture of acetone and hexanes, melted at 154 C. Twomore cryst'allizations from the same solvent pair gave crystals thereofmelting at 162 C. An analytical sample melted at 160-161" C. with A max.241 m E=l5,750, and infrared absorption bands at 3515, 3280, 1745, 1734,1629, and 1243 crnr Similarly, other 21-acylates of 118,17a,2l-trihydroxy- 16B-fluoro-5fl-pregnane-3,20-dione, e.g., whereinthe acyl radical is that of an acid named in the paragraph followingExample 16, are converted to the corresponding 21-acylate ofl1fl,17a,21-trihydroxy 16,8 fiuoro-4-pregnene-3,20-dione.

115,1 7a,21-Trihydr0xy-1 6B-Fluo'r0-L4- Pregnadiene-3,20-Di0ne 21 -Aaerate A solution of 104 mg. of115,1711)1-trihydroxy-16pfluoro-5a-pregnane-3,20-dione 21-acetate, 64mg. of selenium dioxide, 0.06 ml. of acetic acid and 7 ml. of tertiarybutyl alcohol was refluxed for 24 hours under nitrogen. An additional 60mg. of selenium dioxide was added and refluxing was continued foranother 24 hours. The cooled solution was then filtered and evaporatedto dryness at reduced pressure. The residue was taken up in methylenechloride which was then washed with Water, aqueous lead acetate, water,aqueous sodium bicarbonate and water. The dried solution waschromatographed in magnesium silicate. Elution with hexanes containingincreasing amounts of acetone eluted 1l,8,l7|x,2l-1IihYdIOXY-16,8-fiuoro-1,4-pregnadiene-3,20-dione 21--acetate which,

when crystallized twice from a mixture of acetone and 15 radical is thatof an acid named in the paragraph following Example 16, are converted tothe corresponding 21- acylate of11,8,17a,2l-trihydroxy-l6B-fiuoro-1,4pregnadiene-3,20-dione.

Substituting a 21-acylate of 11fi,17a,21- trihydroxy-16fl-fluoro-4-pregnene8,20-dione, e.g., the 2l-acetate or one whose acylradical is that of an acid named in the paragraph following Example 16,as the starting compound in the dehydrogenation reaction described aboveis also productive of the corresponding 21-acylate of 115,170;,21-trihydroxy-16f3-fiu0r0-1,4-pregnadiene-3,2O-dione.

0.6 g. of N-bromoacetamide was added to 1.16 g. of 11[3,17a,21trihydroxy -i 1613 fluoro 1,4 pregnadiene 3,20-dione 2l-acetate in 25ml. of pyridine. The solution Was cooled to C. and sulfur dioxide waspassed over the surface for 10 minutes. The solution was poured into 450ml. of ice water and, after one hour at 5 C., the precipitated 165fluoro 170a,.21 dihydroxy 1,4, 9(11)-pregnatriene-3,20-dione 21-acetatewas collected and dried.

To a solution of the thus-obtained product in ml. of methylene chlorideand m1. of tertiary butyl alcohol was added 0.32 ml. of 70% perchloricacid in 2.5 ml. of water and 0.45 g. of N- bromoacetamide in 5 ml. oftertiary butyl alcohol. The mixture was stirred for 10 minutes at 25-28"C. and 0.5 g. of sodium sulfite in 5 ml. of water was added thereto. Theresulting solution was concentrated at reduced pressure to ml. Thethusproduced 90; bromo 11B,17oc,21 trihydroxy 165 fluoro 1,4 pregnadiene3,20 dione 21 acetate was precipitated therefrom by the slow addition of200 m1. of ice water, collected and dried.

The thus-produced 9a-bromo compound was dissolved in 30 ml. of acetoneand the solution was refluxed for 6.5 hours in the presence of 1.2 g. ofpotassium acetate. The acetone was then removed at reduced pressure andthe steroidal product extracted with methylene chloride. The extractswere washed with water, dried and the thusproduced 95,115 epoxy 17oc,21dihydroxy 16B fluoro 1,4 pregnadiene 3,20 dione 21 acetate was purifiedby chromatography on a column of magnesium silicate developed withhexanes containing increasing amounts of acetone. Crystallization from amixture of acetone and hexanes gave an analytical sample thereof meltingat 152-153 C.

A solution of 0.155 g. of the thus-obtained 96,11,8- oxide in 2 ml. ofmethylene chloride was cooled to C. and then added to a solution of 1.62g. of hydrogen fluoride in dry tetrahydrofuran at -60 C. The solutionwas maintained at 5 C. for 18 hours and then poured into a solution of12 g. of sodium bicarbonate in 120 ml. of ice water. The resultingmixture was extracted with methylene chloride and the extracts weredried and evaporated. The residual 9a,16B difluoro 11B,17oc,21-trihydroxy -l 1,4 pregnadiene 3,20 dione 21 acetate was crystallizedfrom a mixture of acetone and hexanes to give an analytical sample ofthe acetone solvate thereof melting at 110-115 C., )tmax. 239 mE=15,500, and infrared absorption bands at 3350, 1745, 1705, 1664, 1620,1609, 1233, 1045, and 1014 cmr- Following the above procedure,11B,17a,21-trihydroxy- 16,8 fluoro 4 pregene 3,20 dione 21 acetate andother 21 acylates of 11,8,17a,21 trihydroxy 16B fluoro '1 1,4pregnadiene 3,20 dione and of 115,17, 21 trihydroxy 163 fluoro 4pregnene 3,20 dione, e.g., wherein the acyl radical is that of an acidnamed in the paragraph following Example 16, are converted to 9a,16[3difluoro 11fi,17cc,21 trihydroxy 4 pregnene -1 3,20 dione 21 acetate andthe corresponding acylates of 90:,165 difluoro 11{3,17a,21 trihydroxy1,4, preg- 16 nadiene 3,20 dione and 9a,l6fl difiuoro11fi,17a,2ltrihydroxy 4 pregnene 3,20 dione, respectively.

We claim: 1. A compound represented by the formula:

C O O-lower-alkyl wherein Y is selected from the group consisting ofhydroxy-methylene, lower hydrocarbonacyloxymethylene, and carbonyl, andX is selected from the group consisting of wbromo, a-iodo and fl-fluoroand when Y is hydroxymethylene and lower-hydrocarbonacyloxymethylene ithas a stereoconfiguration opposite that of 5-H.

2. 3 3 -1 hydroxy 11 keto 16 8 fluoro 5a pregn 17(20) [cis] en 21 oicacid methyl ester 3 acetate.

3. 3a hydroxy -11- keto -16 8 fluoro 5B pregn 1 17(20) [cis] en 21 oicacid methyl ester 3 acetate.

4. 3p 1 hydroxy 11 keto 16p fluoro 5a pregn 17(20) [cis] en 21 oic acidmethyl ester.

5. 30a hydroxy -11 keto 16,8 fluoro 5B pregn 17(20) a [cis] en 21 oicacid methyl ester. 6. 3,11-diketo 16B fluoro5a-pregn-17(20)-[cis]-en-21-oic acid methyl ester.

7. 3,11-diketo 16B fluoro-SB-pregn-U(20)-[cis]-en- 21-oic acid methylester.

8. A compound represented by the formula:

C O O-lower-alkyl on i F on. 0 i E (2) 3-lower-alkylenedioxy cyclicketals thereof, and (3) 21-lower-hydrocarbonacyloxy esters thereof.

12. 115,21 dihydroxy 16 3 fluoro-5a-pregn-l7(20)- [cis]-en-3-one3-ethylene ketal.

13. 11,8,21 dihydroxy 16B fluoro-513-pregn-17(20)- [cis] -en-3-one3-ethylene ketal.

14. 115,21 dihydroxy 16p fiuoro-5a-pregn-17(20)- [cis]-en-S-one. Y

15. 11,8,21 dihydroxy 16B flu0ro-5/3- pregn-17(20)- [cisJ-en-B-one.

16. 116,21 dihydroxy 16B fluoro-5m-pregn-l7(20)- [cis] -en-3-0ne 2 1acetate.

17. 11,8,21 dihydroxy 165 fluoro-5fi-pregn-17(20)- [cis]-en-3-one21-acetate.

18. A compound represented by the formula:

18 wherein AC is the acyl radical of a lower-hydrocarbon carboxylicacid.

References Cited in the file of this patent UNITED STATES PATENTSSchneider Feb. 12, 1957 2,867,635 Lincoln et a1. Jan, 6, 1959 2,895,972Fried et a1 July21, 1959 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3,027,383 March 27, 1962 Donald E. Ayer et. a1. 7

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 7, line 26, after "-2l-oic" insert acid column 9, line 20, for"concerted" read converted column l3 line 12, for "-[cis]-3one" readcis]en-3-one column 16, lines 37 to 47, the formula s ould appear asshown below instead of as in the patent:

O-lower-alkyl Signed and sealed this 24th day of July 1962.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents

1. A COMPOUND REPRESENTED BY THE FORMULA: